The goal of this proposal is to understand the conformations and conformational transitions of the HIV envelope glycoprotein. X-ray crystallographic analysis will be the principal approach. The structure of gpl4O, the oligomeric (probably trimeric) ectodomain of gpl6O, is a major focus. The applicants can produce SIV gpl4O in large quantities, and will pursue efforts to crystallize it in complex with CD4 (two-domain fragment) and with a specific Fab. They propose to stabilize secreted HIV gpl4O by addition of a trimerizing "isoleucine zipper" at its C-terminus or by mutating certain residues in the gp4l portion to their (more stable) SIV counterparts. They will also link HIV gpl2O to trimerizing zippers, with the similar goal of studying gp120 as an oligomer. They will continue on-going efforts to crystallize ternary complexes of gpl2O with CD4 and various Fab's. The structure of the HIV envelope glycoprotein is of fundamental importance to many vaccine strategies. A three-dimensional framework for understanding HIV antigenic variation is clearly a significant goal.